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Cited by 535SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

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Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement

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McCallum, Matthew, Czudnochowski, Nadine, Rosen, Laura E., Zepeda, Samantha K., Bowen, John E., Walls, Alexandra C., Hauser, Kevin, Joshi, Anshu, Stewart, Cameron, Dillen, Josh R., Powell, Abigail E., Croll, Tristan I., Nix, Jay, Virgin, Herbert W., Corti, Davide, Snell, Gyorgy, Veesler, David·2022·Science
DOI 10.1126/science.abn8652PMC PMC9427005

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo–electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.

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Figures

Fig. 1. CryoEM structure of the SARS-CoV-2 Omicron S trimer reveals a remodeling of the NTD antigenic supersite. (A) Surface rendering in two orthogonal orientations of the Omicron S trimer with one open RBD bound to the S309 (grey) and S2L20 (green) Fabs shown as ribbons. The three S protomers are colored light blue, pink or gold. N-linked glycans are shown as dark blue surfaces. (B) Ribbon diagrams in two orthogonal orientations of the S trimer with one open RBD with Omicron residues mutated relative to Wuhan-Hu-1 shown as red spheres (except D614G which is not shown). (C) The S2L20-bound Omicron NTD with mutated, deleted, or inserted residues rendered or indicated as red spheres. Segments with notable structural changes are shown in orange and labeled. (D) Zoomed-in view of the Omicron NTD antigenic supersite overlaid with the S2X333 Fab (used here as an example of prototypical NTD neutralizing mAb (22)) highlighting the binding incompatibility; the modeled clash between S2X333 W106 and NTD G142D is indicated with an asterisk.
Fig. 1. CryoEM structure of the SARS-CoV-2 Omicron S trimer reveals a remodeling of the NTD antigenic supersite. (A) Surface rendering in two orthogonal orientations of the Omicron S trimer with one open RBD bound to the S309 (grey) and S2L20 (green) Fabs shown as ribbons. The three S protomers are colored light blue, pink or gold. N-linked glycans are shown as dark blue surfaces. (B) Ribbon diagrams in two orthogonal orientations of the S trimer with one open RBD with Omicron residues mutated relative to Wuhan-Hu-1 shown as red spheres (except D614G which is not shown). (C) The S2L20-bound Omicron NTD with mutated, deleted, or inserted residues rendered or indicated as red spheres. Segments with notable structural changes are shown in orange and labeled. (D) Zoomed-in view of the Omicron NTD antigenic supersite overlaid with the S2X333 Fab (used here as an example of prototypical NTD neutralizing mAb (22)) highlighting the binding incompatibility; the modeled clash between S2X333 W106 and NTD G142D is indicated with an asterisk.CC BY · PubMed Central
Fig. 2. SARS-CoV-2 Omicron S mutations outside the NTD and RBD. Ribbon diagram showing a cross-section of the Omicron S glycoprotein (the location of this slice on the S trimer is indicated on the left). Mutated residues T547K, N764K, N856K, N969K, and L981F are shown as red spheres whereas the residues they contact are shown as spheres colored as the protomer they belong to. Black asterisks show the position of residues involved in the prefusion-stabilizing 2P mutations (K986P and V987P) used in all three vaccines deployed in the US. The three S protomers are colored light blue, pink or gold. N-linked glycans are shown as dark blue surfaces.
Fig. 2. SARS-CoV-2 Omicron S mutations outside the NTD and RBD. Ribbon diagram showing a cross-section of the Omicron S glycoprotein (the location of this slice on the S trimer is indicated on the left). Mutated residues T547K, N764K, N856K, N969K, and L981F are shown as red spheres whereas the residues they contact are shown as spheres colored as the protomer they belong to. Black asterisks show the position of residues involved in the prefusion-stabilizing 2P mutations (K986P and V987P) used in all three vaccines deployed in the US. The three S protomers are colored light blue, pink or gold. N-linked glycans are shown as dark blue surfaces.CC BY · PubMed Central
Fig. 3. SARS-CoV-2 Omicron RBD mutations promote escape from a panel of clinical mAbs. (A, RBD antigenic map as determined elsewhere (13). (B) Ribbon diagram of the RBD crystal structure with residue mutated relative to the Wuhan-Hu-1 RBD shown as red spheres. The N343 glycan is rendered as blue spheres. (C to J) Zoomed-in view of the Omicron RBD (blue) superimposed on structures of clinical mAbs (grey) highlighting (black circles) selected residues that interfere with the mAbs: (C) REGN10933, (D) REGN10987, (E) COV2-2196, (F) COV2-2130, (G) LY-CoV555, (H) LY-CoV16, (I) CT-P59, and (J) S309 which does not clash with G339D. Panels A-I were rendered with the crystal structure whereas panel J was generated using the cryoEM model. Binding of the Wuhan-Hu-1 (gray line) or Omicron (red line) RBD to the corresponding mAb was evaluated using surface plasmon resonance (single-cycle kinetics) and is shown underneath each structural superimposition. White and gray stripes are association and dissociation phases, respectively. The black line is a fit to a kinetic model. The decrease in affinity between Wuhan-Hu-1 and Omicron binding is indicated in red. Results are consistent with IgG binding to S ectodomains (fig. S3).
Fig. 3. SARS-CoV-2 Omicron RBD mutations promote escape from a panel of clinical mAbs. (A, RBD antigenic map as determined elsewhere (13). (B) Ribbon diagram of the RBD crystal structure with residue mutated relative to the Wuhan-Hu-1 RBD shown as red spheres. The N343 glycan is rendered as blue spheres. (C to J) Zoomed-in view of the Omicron RBD (blue) superimposed on structures of clinical mAbs (grey) highlighting (black circles) selected residues that interfere with the mAbs: (C) REGN10933, (D) REGN10987, (E) COV2-2196, (F) COV2-2130, (G) LY-CoV555, (H) LY-CoV16, (I) CT-P59, and (J) S309 which does not clash with G339D. Panels A-I were rendered with the crystal structure whereas panel J was generated using the cryoEM model. Binding of the Wuhan-Hu-1 (gray line) or Omicron (red line) RBD to the corresponding mAb was evaluated using surface plasmon resonance (single-cycle kinetics) and is shown underneath each structural superimposition. White and gray stripes are association and dissociation phases, respectively. The black line is a fit to a kinetic model. The decrease in affinity between Wuhan-Hu-1 and Omicron binding is indicated in red. Results are consistent with IgG binding to S ectodomains (fig. S3).CC BY · PubMed Central
Fig. 4. Molecular basis of human ACE2 recognition by the SARS-CoV-2 Omicron RBD. (A) Ribbon diagram of the crystal structure of the Omicron RBD in complex with the ACE2 ectodomain. The S309 and S304 Fab fragments are not shown for clarity. (B to E) Zoomed-in views of the RBD/ACE2 interface highlighting modulation of interactions due to introduction of the N501Y (B), K417N (C), Q493R/Q498R (D) and S477N (E) residue substitutions.
Fig. 4. Molecular basis of human ACE2 recognition by the SARS-CoV-2 Omicron RBD. (A) Ribbon diagram of the crystal structure of the Omicron RBD in complex with the ACE2 ectodomain. The S309 and S304 Fab fragments are not shown for clarity. (B to E) Zoomed-in views of the RBD/ACE2 interface highlighting modulation of interactions due to introduction of the N501Y (B), K417N (C), Q493R/Q498R (D) and S477N (E) residue substitutions.CC BY · PubMed Central

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  1. 10.1016/j.cell.2020.02.058 · DOI · Paper page
  2. 10.1126/science.abh1139 · DOI · Paper page

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Metadata

Authors
McCallum, M., Czudnochowski, N., Rosen, L. E., Zepeda, S. K., Bowen, J. E., Walls, A. C., Hauser, K., Joshi, A., Stewart, C., Dillen, J. R., Powell, A. E., Croll, T. I., Nix, J., Virgin, H. W., Corti, D., Snell, G., & Veesler, D.
Affiliations
  • University of Washington (US)
  • VIR Biotechnology (United States) (US)
  • Howard Hughes Medical Institute (US)
  • University of Cambridge (GB)
  • Lawrence Berkeley National Laboratory (US)
  • Washington University in St. Louis (US)
  • Vir Biotechnology (Switzerland) (CH)
Corresponding author
  • McCallum, Matthew
  • Czudnochowski, Nadine
  • Snell, Gyorgy
  • Veesler, David
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2022-02-25
Volume
375
Issue
6583
Pages
864-868
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.abn8652
PMC
PMC9427005
OpenAlex
W4220861013
Cited by
535
References
85
Citations by year
2026: 25 · 2025: 56 · 2024: 85 · 2023: 122 · 2022: 246
FWCI
62.11
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute (DE-AC02-05CH11231)
  • U.S. Department of Energy (-AC02-05CH11231, Contract No. DE-AC02-05-CH11231, 05CH11231, No. DE-AC02-05-CH11231, DE AC02 05CH11231, DE-AC02-)
  • Burroughs Wellcome Fund (DE-AC02-05CH11231)
  • University of Washington
  • Wellcome Trust (Z/17/Z, 209407/Z/17/Z)
  • Fast Grants
  • National Institutes of Health (S10 OD032290, DE-AC02–05CH11231, 1s10od023476-01, HHSN272201700059C)
  • Office of Science (No. DE-AC02- 05-CH11231, DEAC02–05CH11231, AC02-05CH11231, DE-AC02, 05CH11231, Contract No. DE-AC02-05CH11231)
  • National Institute of General Medical Sciences (DE-AC02-05CH11231, R01GM120553, T32GM008268, P30GM124169)
  • National Institute of Allergy and Infectious Diseases (HHSN272201700059C, DP1AI158186)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords
Omicron variant, spike protein, receptor binding domain, antibody escape, sotrovimab, ACE2 receptor, antigenic shift, spike protein mutations, antibody affinity
MeSH terms
Protein Domains, Broadly Neutralizing Antibodies, Receptors, Coronavirus, Angiotensin-Converting Enzyme 2, SARS-CoV-2, Antigenic Drift and Shift, Antibodies, Monoclonal, Antibodies, Viral, Humans, Models, Molecular, Mutation, Protein Binding, Protein Conformation, Crystallography, X-Ray, Amino Acid Substitution, Cryoelectron Microscopy, Protein Interaction Domains and Motifs, Immune Evasion, Spike Glycoprotein, Coronavirus

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